A variety of chemical compounds and compositions have been reported as having activity against one or more vascular endothelial growth factor receptor tyrosine kinase (VEGF-RTK). Examples include quinoline derivatives such as described in WO 98/13350, aminonicotinamide derivatives (see, e.g. WO 01/55114), antisense compounds (see, e.g. WO 01/52904), peptidomimetics (see, e.g. WO 01/52875), quinazoline derivatives (see, e.g. U.S. Pat. No. 6,258,951) monoclonal antibodies (see, e.g. EP 1 086 705 A1), various 5,10,15,20-tetraaryl-porphyrins and 5,10,15-triaryl-corroles (see, e.g. WO 00/27379), heterocyclic alkanesulfonic and alkane carboxylic acid derivatives (see, e.g. DE19841985), oxindolylquinazoline derivatives (see, e.g. WO 99/10349), 1,4-diazaanthracine derivatives (see, e.g. U.S. Pat. No. 5,763,441), and cinnoline derivatives (see, e.g. WO 97/34876), and various indazole compounds (see, e.g. WO 01/02369 and WO 01/53268).
The synthesis of 4-hydroxy quinolone and 4-hydroxy quinoline derivatives is disclosed in a number of references. For example, Ukrainets et al. have disclosed the synthesis of 3-(benzimidazol-2-yl)-4-hydroxy-2-oxo-1,2-dihydroquinoline. Ukrainets, I. et al., Tetrahedron Lett. 42, 7747-7748 (1995); Ukrainets, I. et al., Khimiya Geterotsiklicheskikh Soedinii, 2, 239-241 (1992). Ukrainets has also disclosed the synthesis, anticonvulsive and antithyroid activity of other 4-hydroxy quinolones and thio analogs such as 1H-2-oxo-3-(2-benzimidazolyl)-4-hydroxyquinoline. Ukrainets, I. et al., Khimiya Geterotsiklicheskikh Soedinii, 1, 105-108 (1993); Ukrainets, I. et al., Khimiya Geterotsiklicheskikh Soedinii, 8, 1105-1108 (1993); Ukrainets, I. et al., Chem. Heterocyclic Comp. 33, 600-604, (1997).
The synthesis of various quinoline derivatives is disclosed in WO 97/48694. These compounds are disclosed as capable of binding to nuclear hormone receptors and being useful for stimulating osteoblast proliferation and bone growth. The compounds are also disclosed as being useful in the treatment or prevention of diseases associated with nuclear hormone receptor families.
Various quinoline derivatives in which the benzene ring of the quinoline is substituted with a sulfur group are disclosed in WO 92/18483. These compounds are disclosed as being useful in pharmaceutical formulations and as medicaments.
Quinolone and coumarin derivatives have been disclosed as having use in a variety of applications unrelated to medicine and pharmaceutical formulations. References that describe the preparation of quinolone derivatives for use in photopolymerizable compositions or for luminescent properties include: U.S. Pat. No. 5,801,212 issued to Okamoto et al.; JP 8-29973; JP 7-43896; JP 6-9952; JP 63-258903; EP 797376; and DE 23 63 459.
A plethora of substituted quinolinone compounds including quinolinone benzimidazolyl compounds and 4-amino substituted quinolinone benzimidazolyl compounds such as 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one have recently been disclosed in references such as WO 02/22598 and WO 2004/043389. Such compounds are disclosed as inhibiting VEGF-RTKs. Such compounds are also disclosed in published United States patent applications U.S. 2002/0107392 and U.S. 2003/0028018 and U.S. Pat. Nos. 6,605,617, 6,774,237, and 6,762,194. Heterocyclic compounds related to benzimidazolyl quinolinones have recently been disclosed in WO 02/18383, U.S. 2002/0103230, and U.S. Pat. No. 6,756,383. Other such compounds are disclosed along with new uses of such compounds in inhibiting serine/threonine kinases and tyrosine kinases are disclosed in WO 2004/018419, and U.S. 2004/0092535, filed on Aug. 19, 2003, and claiming priority to each of the following provisional applications: U.S. Provisional Application No. 60/405,729 filed on Aug. 23, 2002; U.S. Provisional Application No. 60/426,107 filed on Nov. 13, 2002; U.S. Provisional Application No. 60/426,226 filed on Nov. 13, 2002; U.S. Provisional Application No. 60/426,282 filed on Nov. 13, 2002; U.S. Provisional Application No. 60/428,210 filed on Nov. 21, 2002; U.S. Provisional Application No. 60/460,327 filed on Apr. 3, 2003; U.S. Provisional Application No. filed on Apr. 3, 2003; U.S. Provisional Application No. 60/460,493 filed on Apr. 3, 2003; U.S. Provisional Application No. 60/478,916 filed on Jun. 16, 2003; and U.S. Provisional Application No. 60/484,048 filed on Jul. 1, 2003. Still other compounds, method for their synthesis, lactic acid salts thereof, and uses thereof are disclosed in the following patent applications filed on Nov. 5, 2004: U.S. patent application Ser. No. 10/983,174; U.S. patent application Ser. Nos. 10/982,757; and 10/982,5423. Each of the documents in this paragraph is hereby incorporated by reference in its entirety and for all purposes as if fully set forth herein.
Various new compounds have recently been found useful in treating cancer. For example, Gleevec® (imatinib mesylate) is a compound that has recently shown significant activity in a number of different cancers. Gleevec was first made available to patients with Chronic Myeloid Leukemia (CML) in May of 2001. According to the Novartis website, Gleevec is indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) CML in chronic phase. Follow-up is limited. Gleevec is also indicated for the treatment of patients with pH+ CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. Gleevec is also indicated for the treatment of pediatric patients with pH+ chronic phase CML whose disease has recurred after stem cell transplant or who are resistant to interferon-alpha therapy. Gleevec has been approved for use in patients with other cancers such as Gastrointestinal Stromal Tumors (GIST). For example, on Feb. 1, 2002, the FDA granted Novartis approval of Gleevec for the treatment of patients with KIT (CD117) positive unresectable and/or metastatic malignant GIST.
Other new experimental drugs that are currently being tested for efficacy in treating cancer include BAY43-9006 (sorafenib) and Brostallicin. BAY 43-9006 has been granted orphan drug status for the treatment of renal cell carcinoma by the U.S. Food and Drug Administration (FDA). BAY 43-9006 is being evaluated for the treatment of metastatic renal cell carcinoma, an advanced form of kidney cancer. A similar designation has been granted in the European Union by the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMEA). BAY 43-9006 is a novel RAF kinase and VEGFR inhibitor that is intended to prevent tumor growth by combining two anticancer activities: inhibition of tumor cell proliferation and tumor angiogenesis. Brostallicin (PNU-166196) is a synthetic α-bromoacrylic, second-generation DNA minor groove binder structurally related to distamycin A, presently in Phase II trials in Europe and the United States. The compound shows broad antitumor activity in preclinical models and dramatically reduced in vitro myelotoxicity in human hematopoietic progenitor cells compared with that of other minor groove binders. Brostallicin showed a 3-fold higher activity in melphalan-resistant L1210 murine leukemia cells than in the parental line (IC50=0.46 and 1.45 ng/mL, respectively) under conditions in which the cytotoxicity of conventional antitumor agents was either unaffected or reduced.
Although significant strides have been made in the development of pharmaceutical compositions for treating cancer, new methods of treating cancer are required. Especially needed are pharmaceutical compositions and compounds for use in preparing pharmaceutical compositions that are useful in treating drug-resistant cancer and patients with drug-resistant cancers. Also needed are pharmaceutical compositions and compounds that may be administered to patients with drug-resistant cancers in conjunction with known anti-cancer agents.